Coated tablet

ABSTRACT

A main object of the present invention is to provide a novel coated tablet which contains a drug having a guanidino group and does not suffer an obvious color change even when packed in a one-dose pack together with a drug having a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (DMDO) group. The present invention provides a coated tablet characterized in that an uncoated tablet containing a drug having a guanidino group has been coated with a polyvinyl alcohol for film coating which comprises polyvinyl alcohol, acrylic acid, and methyl methacrylate.

This is a U.S. national phase application under 35 U.S.C. §371 ofInternational Patent Application No. PCT/JP2007/061777, filed Jun. 12,2007, and claims the benefit of Japanese Patent Application No.2006-162972, filed Jun. 13, 2006. The International Application waspublished in Japanese on Dec. 21, 2007 as WO 2007/145191. Thedisclosures of all the prior applications are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a coated tablet which is coated with apolyvinyl alcohol copolymer for film coating.

BACKGROUND

For example, it is reported that, when a commercial metforminhydrochloride-containing tablet and a commercial olmesartanmedoxomil-containing tablet are packed together in a one-dose pack, thenthe metformin hydrochloride-containing tablet turns reddish. Thisphenomenon is assumed to be caused by the event that the(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (hereinafter referred to as“DOMDO”) group released from olmesartan medoxomil in the olmesartanmedoxomil-containing tablet is hydrolyzed and converted into diacetyland acetoin, and then these react with the guanidino group of metforminhydrochloride in the metformin hydrochloride-containing tablet. Thisreaction is known as Voges-Proskauel (VP) reaction. As a matter ofcourse, however, the discoloration of drugs is unfavorable and it isconsidered necessary to prevent the discoloration by means of somedevices in drug preparation methods.

In general, for the purpose of preventing or masking discoloration orcoloration of medical and pharmaceutical tablets, uncoated tablets arecoated. Depending on the properties of the compounds in uncoatedtablets, the coating methods and coating agents are selected.

Recently, a polyvinyl alcohol copolymer for film-coating comprisingpolyvinyl alcohol (referred to hereinafter as “PVA”), acrylic acid andmethyl methacrylate has been developed. This was first developed as aagent of capsules shell for solution-filling (see, for example,International Publication WO 02/17848); but owing to its excellent filmformability, physical strength, adhesiveness, oxygen shieldability andthe like, it has come to be applied as a film coating agent (POVACOAT(trade name)) (see, for example, PHARM TECH JAPAN (2005) vol. 21, no. 2,pp. 257-261; Proceedings of the 22th Synposium for Drug Formulation andParticle Design, pp. 77-80 (2005 in Hamamatsu).

SUMMARY OF THE INVENTION

A main object of the present invention is to provide a novel coatedtablet comprising a guanidino group-having drug, which does not exhibitobvious discoloration when packed together with a DMDO group-having drugin a one-dose pack.

The present inventors have intensively studied and found that the aboveobject is achieved by a coated tablet in which an uncoated tabletcontaining guanidino group-having drug is coated with a PVA copolymerfor film-coating (hereinafter simply referred to as “PVA copolymer”)comprising PVA, acrylic acid and methyl methacrylate.

The present invention includes, for example:

-   (1) A coated tablet characterized in that an uncoated tablet    containing a guanidino group-having drug is coated with a PVA    copolymer comprising PVA, acrylic acid and methyl methacrylate.-   (2) The coated tablet of the above (1), wherein the PVA, one    constituent of the PVA copolymer has a degree of polymerization    ranging from 400 to 600 and a degree of saponification ranging from    85 to 90 mol %.-   (3) The coated tablet of the above (1) or (2), wherein the    polymerization ratio of the constituents of the PVA copolymer is    such that PVA is within a range of from 70 to 85% by weight; acrylic    acid is within a range of from 2.0 to 8.0% by weight; and methyl    methacrylate is within a range of from 17 to 21% by weight.-   (4) The coated tablet of any one of the above (1) to (3), which is    coated with the PVA copolymer within a range of from 0.5 to 20.0% by    weight relative to the weight of the uncoated tablet.-   (5) The coated tablet of any one of the above (1) to (4), wherein    the guanidino group-having drug is metformin hydrochloride, camostat    mesilate, zanamivir hydrate, cetrorelix acetate, tegaserodmaleate,    desmopressin acetate, eptifibatide, bivalirudin, ganirelix acetate,    buserelin acetate, famotidine, triptorelin pamoate, pinacidil,    histrelin, thymopentin, adrenochrome guanylhydrazone mesilate,    cimetidine, benexate hydrochloride betadex, gusperimus    hydrochloride, nafamostat mesilate, guanabenz acetate, or    argatroban.-   (6) A one-dose pack comprising at least the coated tablet of any one    of the above (1) to (5) and a tablet that contains a drug having a    (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (DMDO) group.-   (7) The pack of the above (6), wherein the DMDO group-having drug is    olmesartan medoxomil, prulifloxacin, or lenampicillin hydrochloride.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 Color change profile of tablets is shown. The vertical axisindicates color difference (ΔE), and the horizontal axis indicates time(week). In the drawing, -□- indicates the result of coated tablets ofthe present invention of Example 1; -□- indicates the result ofhydroxypropylmethyl cellulose 2910-coated tablets of Comparative Example1; and -- indicates the result of Glycoran tablets (uncoated tablets).

FIG. 2 Color change profile of tablets is shown. The vertical axisindicates color difference (ΔE), and the horizontal axis indicates time(week). In the drawing, -□- indicates the result of coated tablets ofthe invention of Example 1; -⋄- indicates the result of PULLULAN(★)-coated tablets of Comparative Example 2; and -- indicates theresult of Glycoran tablets (uncoated tablets).

DETAILED DESCRIPTION OF THE INVENTION

The “PVA copolymer” used in the present invention is composed of PVA,acrylic acid and methyl methacrylic acid. The polymerization ratio ofeach constituent of the PVA copolymer is not particularly limitedinsofar as it can form a film as the PVA copolymer, and, for example,PVA is preferably within a range of from 70 to 85% by weight, acrylicacid is preferably within a range of from 2.0 to 8.0% by weight; andmethyl methacrylate is preferably within a range of from 17 to 21% byweight. More preferably, PVA is within a range of from 75 to 80% byweight; acrylic acid is within a range of from 2.5 to 7.5% by weight;and methyl methacrylate is within a range of from 17.5 to 20% by weight.

The suitable “PVA” as one of the constituents of the PVA copolymer issuch that the polymerization ratio is, for example, within the range offrom 400 to 600, preferably within the range of from 450 to 550, and thedegree of saponification is, for example, within the range of from 85 to90 mol %, preferably within the range of from 86 to 89 mol %.

The PVA copolymer may be a commercial POVACOAT (registered mark,Nisshin-Kasei) in which PVA, acrylic acid and methyl methacrylate arecopolymerised at a ratio of 80.0% by weight, 2.5% by weight and 17.5% byweight, respectively, and polymerization degree of the said PVA is 500and saponification degree of the said PVA is within a range of from 86.5to 89.0 mol % by weight.

The “guanidino group-having drug” contained in the coated tablet of thepresent invention refers to a drug having a guanidino group or asubstituted guanidino group in the chemical structure of the drug.Herein, the substituted guanidino group refers to the guanidino grouphaving the same or different 1 to 4 substituents at a substitutableposition.

Examples of the substituents may include, for example, straight orbranched alkyl, cyano, nitro, and pyridyl (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl).

Specific examples of the “guanidino group-having drug” may includemetformin hydrocloride, camostat mesilate, zanamivir hydrate, cetrorelixacetate, tegaserod maleate, desmopressin acetate,eptifibatide,bivalirudin, ganirelix acetate, buserelin acetate, famotidine,triptorelin pamoate, pinacidil, histrelin, thymopentin, adrenochromeguanylhydrazone mesilate, cimetidine, benexate hydrochloride betadex,gusperimus hydrochloride, nafamostat mesilate, guanabenz acetate orargatroban.

The “DMDO group-having drug” refers to a drug having a DOMDO group inthe chemical structure of the drug. Specific examples of the “DMDOgroup-having drug” may include olmesartan medoxomil, prulifloxacin orlenampicillin hydrochloride.

In the present invention, an uncoated tablet before being coated may beobtained by granulating an active ingredient such as guanidinogroup-having drug with an excipient, a disintegrant, a binder and so onand milling, followed by mixing the milled powder with a lubricant, andthen compacting into a tablet. As for the excipient, the disintegrant,the binder and the lubricant, those materials which are commonly usedfor preparing tablets may be utilized.

The coated tablet of the present invention may be obtained by coating anuncoated tablet comprising a guanidino group-having drug with a coatingsolution containing a PVA copolymer by an ordinary method.

The content of the PVA copolymer in the coated tablet of the presentinvention is usually within a range of from 0.5 to 20% by weightrelative to uncoated tablet weight, preferably within a range of from1.0 to 10% by weight and more preferably within a range of from 1.5 to5.0% by weight.

In addition, the content of the PVA copolymer in the coating layer maybe usually within a range of from 40 to 80% by weight, preferably withina range of from 45 to 75% by weight and more preferably within a rangeof from 50 to 70% by weight.

An additive commonly used in the coating layer can be contained ifnecessary. The additive is not particularly limited insofar as it is apharmaceutically acceptable additive, and, for example, coating agent(e. g., titanium dioxides, precipitated calcium carbonate), lubricant(e. g., talc), adsorbent (e. g., light anhydrous silicic acid, a hydroussilicon dioxide, magnesium silicate), colorant (e. g., red iron oxide,yellow iron oxide, titanium dioxide, tar dye) can be included. Amongthem, titanium dioxide is more preferable. For example, these additivescan be included in an amount of less than 5% by weight in a coatingsolution together with a PVA copolymer, and can be involved in a coatinglayer through coating an uncoated tablet with the coating solution.

Hereinafter, the present invention is described in more detail byreference to the Examples, Comparative Examples and Test Examples. As amatter of course, the present invention is not limited to the followingexamples.

Example 1

Commercial Glycoran tablets (250 mg, uncoated tablets, byNippon-Shinyaku) of a guanidino group-having drug were obtained; 10,800g of the Glycoran tablets were put into an aeration drying-type coatingmachine (DRC-650 type, by Powrex); using a coating solution prepared bydissolving or suspending 400 g of a PVA copolymer (POVACOAT (registeredtrademark), by Nisshin Kasei), 264 g of titanium dioxide (TIPAQUE A-100,by Ishihara Sangyo) and 136 g of talc (Talc PKP-81, by Fuji TalcIndustrial Co.) in 7,200 g of purified water, coated tablets of thepresent invention coated with the PVA copolymer in a ratio of 3.7% (w/w)relative to the weight of the uncoated tablet were obtained.

Comparative Example 1

Commercial Glycoran tablets (250 mg, uncoated tablets, byNippon-Shinyaku) were obtained; 10,800 g of the Glycoran tablets wereput into an aeration drying-type coating machine (DRC-650 type, byPowrex); using a coating solution prepared by dissolving or suspending435.2 g of hydroxy propylmethyl cellulose 2910, 89.6 g of propyleneglycol and 115.2 g of titanium dioxide (TIPAQUE A-100, by IshiharaSangyo) in 5,760 g of purified water, comparative coated tablets coatedwith the hydroxy propylmethyl cellulose 2910 in a ratio of 4.0% (w/w)relative to the weight of the uncoated tablet, were obtained.

Comparative Example 2

Using a coating agent characterized by oxygen permeation shieldabilitylike POVACOAT, pullulan (by Hayashibara), comparative coated tabletswere produced.

Commercial Glycoran tablets (250 mg, uncoated tablets; byNippon-Shinyaku) were obtained; 10,800 g of the Glycoran tablets wereput into an aeration drying-type coating machine (DRC-650 type, byPowrex); using a coating solution prepared by dissolving 400 g ofpullulan (by Hayashibara) in 4,600 g of pure water, comparative coatedtablets coated with the pullulan in a ratio of 3.7% (w/w) relative tothe weight of the uncoated tablet were obtained.

Test Example 1

Commercial Glycoran tablets (uncoated tablets), coated tablets producedin Example 1 and Comparative Example 1, three tablets, each wererespectively put into a recloseable polyethylene bag (Unipack A-4, bySeisannippon) together with three tablets of a DMDO group-having drugOlmetec (20 mg, by Daiichi-Sankyo), and stored under the conditions of40° C. and 75% RH. After 1, 2, 3 and 4 weeks, the tablets were checkedfor discoloration with a color difference meter (spectral colordifference meter SE2000, by Nippon Denshoku Kogyo).

The results are shown in FIG. 1. When the color difference (ΔE) is 3 orabove, the reddish discoloration of the tablet is recognized with thenaked eye; but significant color change could not be discernible withthe naked eye when the value is not more than 2.5. The color difference(ΔE) means the numerical value converted from the data of colordifference between the aged tablets and the original tablets before thetest.

As is obvious from FIG. 1, the coated tablets of the present inventionproduced in Example 1 were remarkably prevented from being discolored,as compared with the Glycoran tablets and the hydroxypropylmethylcellulose 2910-coated tablets produced in Comparative Example 1.

Test Example 2

Commercial Glycoran tablets (uncoated tablets), coated tablets producedin Example 1 and Comparative Example 2, three tablets, each wererespectively packed with cellophanpoly (by Nihonshokai) together withthree tablets of a DMDO group-having drug Olmetec (20 mg, byDaiichi-Sankyo), and stored under the conditions of 40° C. and 75% RH.After 1 and 2 weeks, the tablets were checked for discoloration with acolor difference meter (spectral color difference meter, SE2000, byNippon Denshoku Kogyo).

The results are shown in FIG. 2. When the color difference (ΔE) is 3 orabove, the reddish discoloration of the tablet is recognized with thenaked eye; but any clear color change could not be discernible with thenaked eye when the value is not more than 2.5.

As is obvious from FIG. 2, the coated tablets of the present inventionproduced in Example 1 were remarkably prevented from being discolored,as compared with the Glycoran tablets produced in Comparative Example 2.

INDUSTRIAL APPLICABILITY

As described above, the coated tablet of the present invention canmarkedly prevent reddish discoloration reaction that could occur whenthe tablet was kept in contact with or in close contact with a DMDOgroup-having drug. Accordingly, the coated tablet of the presentinvention is useful since the color change of the tablet can beprevented even when packed in a one-dose pack together with a DMDOgroup-having drug.

1. A coated tablet prepared by coating an uncoated tablet containing aguanidino group-having drug, with a polyvinyl alcohol copolymer forfilm-coating comprising polyvinyl alcohol, acrylic acid and methylmethacrylate.
 2. The coated tablet as claimed in claim 1, wherein thepolyvinyl alcohol, one constituent of the polyvinyl alcohol copolymerfor film-coating has a polymerization degree of from 400 to 600 and asaponification degree of from 85 to 90 mol %.
 3. The coated tablet asclaimed in claim 1, wherein the polymerization ratio of the constituentsof the polyvinyl alcohol copolymer for film-coating is such thatpolyvinyl alcohol is within a range of from 70 to 85% by weight; acrylicacid is within a range of from 2.0 to 8.0% by weight; and methylmethacrylate is within a range of from 17 to 21% by weight.
 4. Thecoated tablet as claimed in claim 1, which is coated with the polyvinylalcohol copolymer for film-coating within a range of from 0.5 to 20.0%by weight relative to the weight of the uncoated tablet.
 5. The coatedtablet as claimed in claim 1, wherein the guanidino group-having drug ismetformin hydrochloride, camostat mesilate, zanamivir hydrate,cetrorelix acetate, tegaserod maleate, desmopressin acetate,eptifibatide, bivalirudin, ganirelix acetate, buserelin acetate,famotidine, triptorelin pamoate, pinacidil, histrelin, thymopentin,adrenochrome guanylhydrazone mesilate, cimetidine, benexatehydrochloride betadex, gusperimus hydrochloride, nafamostat mesilate,guanabenz acetate, or argatroban.
 6. A one-dose pack comprising thecoated tablet of claim 1 and a tablet comprising a drug having a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (DMDO) group.
 7. The pack asclaimed in claim 6, wherein the DMDO group-having drug is olmesartanmedoxomil, prulifloxacin, or lenampicillin hydrochloride.